PDBsum entry 1cnn

Toxin

PDB id

1cnn

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Contents

			Protein chain

					27 a.a.

PDB id:

1cnn

Links
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Name:

Toxin

Title:

Omega-conotoxin mviic from conus magus

Structure:

Omega-conotoxin mviic. Chain: a. Synonym: mviic. Engineered: yes

Source:

Synthetic: yes. Other_details: the peptide was chemically synthesized. The sequence of the peptide is naturally found in the venom duct of conus magus (magus cone).

NMR struc:

17 models

Authors:

K.J.Nielsen,D.Adams,L.Thomas,T.Bond,P.F.Alewood,D.J.Craik,R.J.Lewis

Key ref:

K.J.Nielsen et al. (1999). Structure-activity relationships of omega-conotoxins MVIIA, MVIIC and 14 loop splice hybrids at N and P/Q-type calcium channels. J Mol Biol, 289, 1405-1421. PubMed id: 10373375 DOI: 10.1006/jmbi.1999.2817

Date:

20-May-99

Release date:

31-May-00

PROCHECK

	Headers

	References

Protein chain

P37300 (O17C_CONMA) - Omega-conotoxin MVIIC (Fragment) from Conus magus

Seq: Struc:					29 a.a. 27 a.a.*

Key:

Secondary structure

* PDB and UniProt seqs differ at 1 residue position (black cross)

DOI no: 10.1006/jmbi.1999.2817	J Mol Biol 289:1405-1421 (1999)
PubMed id: 10373375

Structure-activity relationships of omega-conotoxins MVIIA, MVIIC and 14 loop splice hybrids at N and P/Q-type calcium channels.
K.J.Nielsen, D.Adams, L.Thomas, T.Bond, P.F.Alewood, D.J.Craik, R.J.Lewis.

ABSTRACT

The omega-conotoxins are a set of structurally related, four-loop, six cysteine containing peptides, that have a range of selectivities for different subtypes of the voltage-sensitive calcium channel (VSCC). To investigate the basis of the selectivity displayed by these peptides, we have studied the binding affinities of two naturally occurring omega-conotoxins, MVIIA and MVIIC and a series of 14 MVIIA/MVIIC loop hybrids using radioligand binding assays for N and P/Q-type Ca2+channels in rat brain tissue. A selectivity profile was developed from the ratio of relative potencies at N-type VSCCs (using [125I]GVIA radioligand binding assays) and P/Q-type VSCCs (using [125I]MVIIC radioligand binding assays). In these peptides, loops 2 and 4 make the greatest contribution to VSCC subtype selectivity, while the effects of loops 1 and 3 are negligible. Peptides with homogenous combinations of loop 2 and 4 display clear selectivity preferences, while those with heterogeneous combinations of loops 2 and 4 are less discriminatory. 1H NMR spectroscopy revealed that the global folds of MVIIA, MVIIC and the 14 loop hybrid peptides were similar; however, several differences in local structure were identified. Based on the binding data and the 3D structures of MVIIA, GVIA and MVIIC, we have developed a preliminary pharmacophore based on the omega-conotoxin residues most likely to interact with the N-type VSCC.

Selected figure(s)



	Figure 7. Figure 7. Profiles of (a) relative selectivity shown in rank order and (b) absolute potency shown in rank order within the four groups defined in (a), namely XCXC, XCXA, XAXC and XAXA.		Figure 9. Figure 9. (a) Solid surface (1.4 Å radius) of six residues likely to be involved in N-type VSCC binding interactions. These are numbered according to (1) Tyr13 (from MVIIA), (2) Arg10 (MVIIA), (3) Leu11 (MVIIA), (4) Arg21 (MVIIA), (5) Tyr22 (GVIA), and (6) Lys24 (GVIA). The backbone of MVIIA (pink) is shown in correct orientation for binding. In (b), (c) and (d) the same surface as in (a) is shown, but in dot format. Inside this surface is shown the heavy atoms of (b) MVIIA, (c) GVIA (backbone blue), and (d) MVIIC (backbone purple). The side-chains are color-coded in the following manner: yellow (hydrophobic), green (polar), red (negative) and blue (positive). Binding surfaces which are optimally filled are labeled in pink. Residues that form a possible clash (negative interaction) are denoted in red (site 5 and R9 of MVIIC).

Figures were selected by the author.

Literature references that cite this PDB file's key reference

PubMed id

Reference

18522941

C.I.Schroeder, J.Ekberg, K.J.Nielsen, D.Adams, M.L.Loughnan, L.Thomas, D.J.Adams, P.F.Alewood, and R.J.Lewis (2008).
Neuronally micro-conotoxins from Conus striatus utilize an alpha-helical motif to target mammalian sodium channels.

J Biol Chem, 283, 21621-21628.

19300539

J.G.McGivern (2007).
Ziconotide: a review of its pharmacology and use in the treatment of pain.

Neuropsychiatr Dis Treat, 3, 69-85.

16826542

U.C.Marx, N.L.Daly, and D.J.Craik (2006).
NMR of conotoxins: structural features and an analysis of chemical shifts of post-translationally modified amino acids.

Magn Reson Chem, 44, S41-S50.

15880145

L.Wen, S.Yang, H.Qiao, Z.Liu, W.Zhou, Y.Zhang, and P.Huang (2005).
SO-3, a new O-superfamily conopeptide derived from Conus striatus, selectively inhibits N-type calcium currents in cultured hippocampal neurons.

Br J Pharmacol, 145, 728-739.

14696181

C.Bernard, G.Corzo, S.Adachi-Akahane, G.Foures, K.Kanemaru, Y.Furukawa, T.Nakajima, and H.Darbon (2004).
Solution structure of ADO1, a toxin extracted from the saliva of the assassin bug, Agriosphodrus dohrni.

Proteins, 54, 195-205.

PDB code:

1lmr

15166237

J.Mould, T.Yasuda, C.I.Schroeder, A.M.Beedle, C.J.Doering, G.W.Zamponi, D.J.Adams, and R.J.Lewis (2004).
The alpha2delta auxiliary subunit reduces affinity of omega-conotoxins for recombinant N-type (Cav2.2) calcium channels.

J Biol Chem, 279, 34705-34714.

PDB codes:

1tr6 1ttl

12441339

D.J.Adams, A.B.Smith, C.I.Schroeder, T.Yasuda, and R.J.Lewis (2003).
Omega-conotoxin CVID inhibits a pharmacologically distinct voltage-sensitive calcium channel associated with transmitter release from preganglionic nerve terminals.

J Biol Chem, 278, 4057-4062.

PDB codes:

1tt3 1ttk

12824165

I.A.Sharpe, L.Thomas, M.Loughnan, L.Motin, E.Palant, D.E.Croker, D.Alewood, S.Chen, R.M.Graham, P.F.Alewood, D.J.Adams, and R.J.Lewis (2003).
Allosteric alpha 1-adrenoreceptor antagonism by the conopeptide rho-TIA.

J Biol Chem, 278, 34451-34457.

12006587

K.J.Nielsen, M.Watson, D.J.Adams, A.K.Hammarström, P.W.Gage, J.M.Hill, D.J.Craik, L.Thomas, D.Adams, P.F.Alewood, and R.J.Lewis (2002).
Solution structure of mu-conotoxin PIIIA, a preferential inhibitor of persistent tetrodotoxin-sensitive sodium channels.

J Biol Chem, 277, 27247-27255.

PDB code:

1r9i

11040337

J.Melena, G.Chidlow, and N.N.Osborne (2000).
Blockade of voltage-sensitive Na(+) channels by the 5-HT(1A) receptor agonist 8-OH-DPAT: possible significance for neuroprotection.

Eur J Pharmacol, 406, 319-324.

10822250

K.J.Nielsen, T.Schroeder, and R.Lewis (2000).
Structure-activity relationships of omega-conotoxins at N-type voltage-sensitive calcium channels.

J Mol Recognit, 13, 55-70.

The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.